Biomarkers may enable blood test for early Alzheimer’s disease, explain sex disparity

Key takeaways:

• Women, but not men, at risk for or who have early dementia exhibited free carnitine deficiency.
• Free-carnitine and acetyl-L-carnitine tests were comparable to CSF measures for determining disease status.

Women with amnestic mild cognitive impairment and early Alzheimer’s disease had lower levels of acetyl-L-carnitine and its derivative free carnitine, which may enable blood-based biomarker detection of the disease, according to a study.

However, men at risk for or with dementia experienced decline only in acetyl-L-carnitine (LAC), according to the study results, published in Molecular Psychiatry.

“The results ... might explain the differences by sex in Alzheimer’s disease, with more women than men having dementia,” Benedetta Bigio, PhD, research assistant professor in the department of psychiatry at NYU Grossman School of Medicine and researcher at the Nathan S. Kline Institute for Psychiatric Research, said in a related press release.

Further, the magnitude of free carnitine deficiency reflected the severity of the disease in women.

Both LAC and free carnitine are essential for healthy brain function and cell metabolism regulation, according to the release. Previous research performed by this team revealed that LAC plays a key role in mitochondrial metabolism in the hippocampus, which helps regulate memory and is often one of the first areas damaged by AD.

The researchers theorized that LAC and free carnitine could act as blood biomarkers for identifying AD as well as patients who may be at greater risk for developing dementia, allowing for early intervention. Developing a blood test for dementia based on these biomarkers would be far easier and less invasive than current cerebrospinal fluid tests for amyloid beta and tangled tau protein, they added.

This inspired the researchers to perform an analysis of data from two independent study cohorts to determine how sex impacts the levels of LAC and free carnitine in men and women with amnestic mild cognitive impairment (aMCI) and early dementia, as well as how these biomarkers compare in diagnostic accuracy to current CSF tests.

The analysis included 125 adults from Brazil and California cohorts — the latter of which served as a confirmatory cohort — 93 of whom had varying degrees of cognitive impairment, including AD (n = 41), Lewy body dementia (n = 14) and aMCI (n = 38). The remaining 32 were healthy and of similar age, weight and education to the other group.

The researchers found that women with aMCI and early AD had lower plasma levels of free carnitine compared with controls (32.45 ± 1.43 mol/L vs. 39.29 ± 1.79 mol/L; P = .02).

No significant difference in free carnitine was observed between men with cognitive impairment and healthy controls.

The analysis also replicated prior results, showing decreased levels of LAC among men and women with aMCI (8.4 ± 1.18 mol/L) and AD (7.89 ± 1.13 mol/L) compared with age- and sex-matched healthy controls (9.52 ± 1 mol/L; P = .02).

In the first cohort, the researchers observed a significant correlation between free carnitine concentrations and the severity of cognitive impairment among women, as assessed by the Mini Mental State Exam (P = .007) and the Wechsler Memory Scale (P = .002). No such correlation was observed among men. This finding was replicated in the second cohort using the Clinical Dementia Rating sum-of-boxes (CDR-SB) score, with women with lower concentrations of free carnitine having the highest CDR-SB score after controlling for education and clinical characteristics (P = .04).

Finally, participants with lower free carnitine levels demonstrated greater beta-amyloid accumulation and higher t-Tau levels in their CSF. According to computational analyses, the researchers found that LAC and free carnitine are at least as accurate as these traditional measures in reflecting disease status. By combining both techniques, the team’s accuracy in diagnosing AD rose from more than 80% to 93%.

“Our findings offer the strongest evidence to date that decreased blood levels of acetyl-L-carnitine and free carnitine could act as blood biomarkers for identifying those who have Alzheimer’s disease, and potentially those who are at greater risk of developing early dementia,” Bigio said in the release.

“Because declines in acetyl-L-carnitine and free carnitine tracked closely with the severity of Alzheimer’s disease, the molecular pathways involved in their production offer other possible therapeutic targets for getting at the root cause of the disease and potentially intervening before permanent brain damage occurs,” she added.

Future research should investigate the root sources of LAC, how it is produced and how the molecule affects brain chemistry, according to the researchers. The study team’s goal is to identity other biomarkers in the brain that could help to diagnose and potentially treat AD.

Reference:

• Study advances possible blood test for early-stage Alzheimer’s disease. https://nyulangone.org/news/study-advances-possible-blood-test-early-stage-alzheimers-disease. Published Jan. 8, 2025. Accessed Jan. 16, 2025.